Project Summary/Abstract Allergic diseases, including asthma, allergic rhinitis, and food allergy, have been steadily increasing in incidence and disproportionately affect children. Allergic responses can be triggered rapidly upon exposure to an allergen that binds to IgE antibodies on mast cells and basophils; these cells then degranulate and release potent pro-inflammatory mediators. If this response occurs systemically, known as anaphylaxis, it can be life- threatening. However, despite the importance of IgE in allergic disease, the intrinsic mechanisms that regulate IgE-expressing B cells remain unclear. Recent technical advances have made it possible to directly detect and visualize IgE+ B cells in mice, revealing that IgE+ B cells undergo an abortive germinal center phase and are predisposed to differentiate into short-lived plasma cells. These properties of IgE+ B cells restrain IgE responses and therefore may help protect against allergy and anaphylaxis in healthy individuals. Recent studies have demonstrated that the distinct features of mouse IgE+ B cells are largely due to the expression of the membrane IgE B cell receptor, which has weak, chronic signaling activity compared with other isotypes. The overall objective of this study is to determine how B cell receptor signaling regulates IgE+ B cell responses in mice and whether these findings are applicable to human B cells. The specific goals of this study are to 1) elucidate the mechanisms by which B cell receptor signaling regulates IgE plasma cell responses, 2) to characterize the role of B cell receptor signaling in the dynamics of IgE+ B cells in germinal centers, and 3) to determine whether human IgE B cell receptors regulate IgE responses in a similar fashion to mouse IgE B cell receptors. The results from these studies will help us understand how potent IgE-mediated allergic responses are controlled at a molecular level. .